formulation and evaluation of fast disintegrating tablet by using superdisintegrants and RP-HPLC method development of prepered tablet of Amlodipine besilate and Candesartan cilexetil

1. Formulation and evaluationof fast disintegrating tablet and development of
rp-hplcmethod for estimation of amlodipine besilate and candesartan cilexetil
Shivnagar Vidya Prasarak Mandal’s
College of Pharmacy, Malegaon (Bk), Baramati
2014-2015
Presented By:-
Miss. Pooja. Ganesh Deshmukh
Second Year M. Pharmacy, Sem-IV (QAT)
Under the guidance of
Prof. G. K. Dyade
Research Guide
Dr. R. B. Jadhav
Co-Guide

2. • INTRODUCTION
• LITERATURE REVIEW
• AIM AND OBJECTIVES
• PLAN OF WORK
• DRUG AND EXCIPIENT PROFILE
• MATERIALS AND EQUIPMENTS
• METHODOLOGY AND RESULT
• CONCLUSION
• REFERENCES
2

3. •A solid dosage form containing medicinal substance which disintegrates
quickly within a matter of second when placed on tablet.
•FORMULATION ASPECT
Drug candidate Excipient
Free from bitter taste
Lower than 20 mg
Small to moderate molecular weight
Good solubility in water and saliva
Ability to disperse into the epithelium
of upper GIT
Ability to permeate oral mucosal
time
Dissolve in oral cavity within short
time
Drug loading capacity
Unaffected with change in humididity
and temperature.
Excipient % Used
Superdisintegra
nt
1-15 %
Binder 5-10 %
Diluent 0-85 %
Antistatic agent 0-10 %
3

4. Superdisintegrants
• Good compressibility & flow
property
• Poor solubility
• Poor gel formation capacity
• Good hydration capacity
• Complexation
• Intragranular
• Extragranular
• Internal & external addition
• Porocity And Capillary Action
• Swelling
• Particle Repulsion Forces
• Elastic Recovery
• Enzymatic Reaction
• Heat Of Wetting
• Release Of Gases
Method of addition
Selection of
Superdisintegrants
Mechanism of Superdisintegrants
4

5. • Binders: To achieve the required sensory and melting characteristics and fast
release of drug.
• Lubricants: For masking tablet more palatable
• Filers: To improve texture of the tablet and consistently improve disintegration
of tablet in mouth.
• Glidents : To improve the flow ability of the powder
Adventages Disadventages
Accurate dosing
Improved bioavaliability
Rapid action
Patient complience
Ease to administer
Enhance palatability
Mechanical strength of
tablet
Bad taste drug are dificult to
formulate
Drug & dosage form
stability
5

6. Techniques for preparation of Oral
Disintegrating Tablet
• Technique
Conventional patented
Hot process
•Molding
•Sublimation
•Compaction
•Mass
extrusion
•Cottan candy
process
Cold
process
•Direct
compresson
•Fast
dissolving
•Lyophilizatio
n
•nanonization
• Zydis
• Orosolv
• Wowtab
• Flashtab
• Advatab
• Frosta
•
Shearform
• Ceform
•
Phrmaburst 6

7. Analytical chemistry
analytical chemistry is the branch of science that uses advanced technology in
determining the composition by analytical technique
Analysis can be divided into two types
A. Qualitative analysis
B. Quantitative analysis
C. Structural Analysis
• Analytical method
A. Classical Method- Gravimetry, Titrimery
B. Instrumental Method- Electroanalytical, Spectroscopy, Thermal,
Radiometric, NMR Spectroscopy
7

8. Types of chromatography
Basis of
classification
Chromatographic types
chromatographic bed
shape
Column chromatography
Plane chromatography
Paper
Thin layer
Physical state Gas chromatography
Liquid chromatography
Affinity Dye affinity chromatography
Metal affinity chromatography
Seperation Ion exchange chromatography
Size exclusion chromatography
Reverse phase chromatography
Normal phase chromatography
Special technique HPLC
Pyrolysis
Moving bed chromatography
8

9. A. Mobile phase Reservoir and solvent
system treatment
B. Solvent delivery system-
Constant pressure pump
Constant Flow pump
C. Sample Injection system-
Septum injector
Stop flow septum injector
D. Column
E. Detectors –
1. Solute property detector-
a) Refractive index detector
b) Conductivity detector
2. Bulk property detector-
a) UV detectetor
b) Floroscence detector
Component of HPLC
9

10. Based on Types Characteristics
Seperation Adsorbtion •Based on polarity of sample
•Highly polar compound eluate faster
partition • Based on solubility of sample in SP and MP
Ion exclusion • Based on electrostatic interaction between ion
exchanger &ionic solutes
• Dissociated molecules elutes faster
• Analysis of organic acid
Size-
exclusion
• Based upon size
• Bigger molecule faster elutes
• Determination of macromolecules and qualification
oligomers
Mode Normal mode • Based on partition equilibrium
• Polarity of SP is Higher than the MP
• Mobile phase contains organic solvent
• high polarity MP causes a faster elution
Reverse
phase
• Based on partition equilibrium
• Polarity of SP is lower than MP
• Mobile phase contains organic & aqueous solvent
• lower polarity MP causes a faster elution
eluation Gradient
Iso-cratic
• Change in mobile phase
• One mobile phase is used
10

11. HPLC method development
11
method selection
chromatographic
condition
selectivity
optimization
System
optimization
Method
optimization
Analytical profile, Stability profile, Solubility profile
Shape & Size of particle size, Pore size, Surface area,
End capping, column load, column temperature
Selection of stationary phase, mobile
phase, Buffer & Buffer pH, Detector
Sample preperation
Column packing, Column dimension

12. Analytical Method Validation
Characteristics Acceptance criteria
Linearity > 0.999
Accuracy 98-102 %
Specificity No interference
Precision RSD <2%
Detection limit S/N > 2 or 3
Quantitation limit S/N > 10
Linearity
Range
Accuracy
Specificity
Precision
Robustness
LOD/LOQ
•Validation: “ A documented programme which provides a high
degree of assurance that a specific process will consistently
produce a product meeting its pre –determined specification and
quality attributes ”
12

13. System Suitability Parameters
• Retention Time-The Time Elapsed
Between The Injection Of The Sample
Components Into The Column And Their
Detection .
• Peak Assymetry & Tailing Factor
AS= B/A
• Therotical Plate
HETP =L/N
ICH Guidelines
USP Therotical plate
13

14. Aim-
Formulation and evaluation of Fast Disintegrating Tablet and
RP-HPLC method development
Objective
• To formulate Fast Disintegrating Tablet
• To develop RP-HPLC analytical method.
• To evaluate Pre-compression & Post compression parameters
• To perform stability studies includes stability indicating assay method
Aim & Objective
14

15. PLAN OF WORK
Selection of Drug
Literature
Survey
Selection of FDT
Designing of Fast
Disintegrating Tablet
Selection of
Chromatographic
condition
Formulation &
Evaluation of
Developed Formulation
Analytical method
Validation
Stability Studies
Result & Discussion
15

16. 16
SR.
NO
TITAL JOURNAL YEAR
1 Mouth Dissolving Tablet: An overview on Future
Compaction in oral formulation Technogies
Der Pharmacia
Sinica
2010
2 Formulation and Evaluation of fast dissolving tablet
of candesartan cilexetil using natural and synthetic
superdisintegrant.
Journal of Applied
Pharmacy
2011
3 Formulation and Evaluation of oral fast
disintegranting tablets by using Amlodipine Besylate
solid dispersion by direct compression method.
Der. Pharmacy
Letter
2012
4 Formulation ,optimization and Evaluation of Bi-layer
Immediate release tablets of Telmisartan and
Amlodipine Besilate using full factorial design.
International
Journal of
Pharmacy and
Pharmaceutical
Sciences
Research
2013
5 Fast Dissolving Dosage Form. An Overview World Jornal of
Pharmaceutical
Research
2016
6 Fast Dissolving Tablets: A Novel Approach to European 2017

17. 17
SR.
NO
TITAL JOURNAL YEA
R
8 Stability indicating RP-HPLC method for the
determination of candesartan in pure and pharmaceutical
formulation.
Int. .J..Pharm.
Ind. Res.
2011
9 Development and Validation of a Simultaneous HPLC
Method for Quantification of Amlodipine Besylate and
Metoprolol Tartrate in Tablets.
J. Pharm. Sci.
Tech.
2012
10 Method Development, Validation and Stability Analysis by
RP-HPLC Method for the Simultaneous Estimation of
Candesartan Cilexetil and Levocetrizine Hydrochloride.
Int. J. Med.
Nanotechnol,
Mednano
Publications.
2014
11 Development and validation of RP-HPLC Method for
simultaneous estimation of Atenolol and Amlodipine in
bulk and tablet dosage form.
Int. J. Pharm. 2014
12 Development and Validation of RP - HPLC Method for the
Simultaneous Determination of Hydrochlothaizide,
Amlodipine Besylate and Telmisartan in Bulk and
Pharmaceutical Formulation.
Orient. J.
Chem.
2014
13 Stability indicating RP-HPLC method development and
validation for the simultaneous estimation of candesartan
cilexetil and hydrochlorothiazide in bulk and tablet
dosage form.
Der. Pharma.
Lett.
2015

18. Drug profile
Drug Amlodipine besilate Candesartan cilexetil
Chemical structure
Molecular weight 567.1 610.671
Molecular formula C26 H31 CL N2 O 8 S C33 H34 N6 O6
Solubility Slightly soluble in water, freely
soluble in methanol, Sparingly
soluble in ethanol
Freely soluble in methylene
chloride,Methanol,Acetonitrile
Bioavailability 64-90 % 15 %
Log P 2.22 6.1
Dose 2.5-10 mg 2-32 mg
18

19. drug Amlodipine besilate Candesartan cilexetil
Protein binding 93 % > 99 %
Half life 30-50 hours 9 hours
Melting point 201‫ﹾ‬c 163‫ﹾ‬c
Maerketed preperation Asomex
Esam
Eslova
S-Amlovas
S-Amidoich
Candesar
Candestan
Candelong
IPSITA
19

20. Excipient Profile
Excipie
nt name
Cross
carmelose
sodium
Ethyl
cellulose
HPMC
Microcrystalline
sodium
Mannitol
Synonyms Ac-Di-Sol
Ethocel,
Aquacoat
Cellulose,2-0H
propyl methyl
cellulose
Avicel PH, Cellusegel Manna sugar
Descriptio
n
White, free
flowing
powder
White to off-white
colour, odourless
White to creamy
with granular
powder
White ,odourless, Free
flowing crystalline
powder
White crystalline,
free flowing
powder
Physical
properties
MP->205‫ﹾ‬c
Freely soluble in
methanol,
insoluble in water
MP-190‫ﹾ‬c
Soluble in water
Insoluble in water,
ether, slightly soluble in
NAOH
Soluble in water,
alcohol, insoluble
in ether
Application
s
• Tablet &
Capsule
disintegrants
• Dissolution
agent
• Binder
• Coating
material
• Disintegrating
• Tablet binder
• Coating
material
• Thickning
agent
• Suspending
agent
• Wetting agent
•Tablet binder
•Diluent
•Lubricant
•Disintegrants
Tablet diluent
Sweetening agent
20

21. Name of ingredients Name of the Supplier
Amlodipine besilate Swapnaroop
Candesartan cilexetil Swapnaroop
HPMC Bombay Research Lab
Ethyl cellulose Mahendra Chemicals
Cross carmelose
Sodium
Fine Chemicals
MCC Fine Chem Reserch Lab
Mannitol Loba Chemie
Potassium dihydrogen
orthophosphate
Loba Chemie
Sodium hydroxide Poona Chemicals Lab
Methanol (HPLC) Merck Chemicals
Acetonitrile (HPLC) Merck Chemicals
Water (HPLC) Merck Chemicals
Methanol (HPLC) Merck Chemicals
Glacial acetic acid Merck Chemicals
Name of Equipment Manufacturer/ model
Analytical Balance Afcoset
Ultrasonication Shimdzu
UV Spectroscopy Shimadzu
HPLC Shimadzu
Digiital pH meter HANNA
USP Dissolution Apparatus Electrolab
Hot Air oven YORK
Tablet Hardness tester Monsanto
Friability Cambell eletronic
Vernier Calliper Mitutoyo Digimatic
Calliper
Tablet Disintegration Machine Electrolab
Tablet Punching Machine Karnavati
Stability Chamber Thermolab
Photostability Chamber Newtronic Lifecare
FT-IR JASCO FT-IR
Method and material
21

22. 1. ANALYTICAL METHOD DEVELOPMENT
2. PRE-FORMULATION STUDY
• Fourier transform infrared analysis (FTIR)
• Differential scanning calorimetry
3. FORMULATION AND DEVELOPMENT
• Formulation of Fast Disintegrating Tablet
• Post-compression parameter
• Evaluation of optimized tablet
4. RP-HPLC METHOD DEVELOPMENT
• System Suitability Testing
• Method Validation
• Stability Studies
22

23. Sr.N
o.
Ingredient Formulation code
F1 F2 F3 F4
1 Amlodipine besilate 5 5 5 5
2 Candesartan
cilexetil
8 8 8 8
3 HPMC 50 100 50 100
4 Ethyl cellulose 25 25 50 50
5 Cross carmelose 10 10 10 10
6 Microcrystalline
Sodium
40 40 40 40
7 Mannitol 150 100 125 75
Total weight (mg) 288 288 288 288
Formulation of Fast Disintegrating Tablet
23

24. ANALYTICAL METHOD DEVELOPMENT
• Determination of λmax of Amlodipine besilate & Candesartan
cilexetil in Methanol
Spectrum of Amlodipine besilate Spectrum of Candesartan cilexet
24

25. Calibration Curve of Amlodipine besilate in Methanol
Concentration Absorbance
0 0
4 0.158
8 0.302
12 0.444
16 0.596
20 0.739
24 0.889
y = 0.036x + 0.005
R² = 0.999
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 4 8 12 16 20 24 28
Absorbance
Concentration
Calibration curve of Amlodipine besilate in methanol
Series1
Linear (Series1)
SOLVENT METHANOL
λ max (nm) 237.5 nm
(R2) 0.999
Regression equation y= 0.036x-0.005
Intercept (a) 0.005
Slope (b) 0.036
25

26. Calibration curve of Amlodipine besilate in phosphate buffer
6.8 pH
Concentratio
n
Absorbance
0 0
1 0.080
2 0.150
3 0.249
4 0.340
5 0.446
6 0.520
7 0.626
8 0.730
9 0.823
10 0.928
SOLVENT METHANOL
λ max (nm) 237nm
(R2) 0.999
Regression equation y= 0.093x-0.022
Intercept (a) 0.022
Slope (b) 0.093
26

27. Calibration curve of Candesartan cilexetil in methanol
y = 0.023x + 0.001
R² = 0.999
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 4 8 12 16 20 24 28
Absorbance
Concentration
Calibration curve of Candesartan cilxetil in methanol
Series1
Linear (Series1)
Concentration Absorbance
0 0
4 0.099
8 0.193
12 0.285
16 0.386
20 0.476
24 0.573
SOLVENT METHANOL
λmax (nm) 254nm
(R2) 0.999
Regression equation y= 0.023x-0.001
Intercept (a) 0.001
Slope (b) 0.023
27

28. Calibration curve of Candesartan cilexetil in phosphate
buffer 6.8 pH
y = 0.064x - 0.025
R² = 0.997
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 1 2 3 4 5 6 7 8 9 10
Absorbance
Concentration
Calibration curve of Candesartan cilexetil in
phosphate buffer 6.8
Series1
Linear (Series1)
Concentration Absorbance
0 0
1 0.030
2 0.090
3 0.162
4 0.224
5 0.294
6 0.362
7 0.430
8 0.491
9 0.554
10 0.621
SOLVENT METHANOL
λ max (nm) 254 nm
(R2) 0.997
Regression equation y= 0.064x-0.025
Intercept (a) 0.025
Slope (b) 0.064 28

29. FTIR & DSC of Amlodipine besilate
Functional
group
Vibrational Frequencies
(cm-1)
Observed Reported
O-H
Stretching
3143 3300-2500
C-H
Stretching
2926 3300-2500
C=O
Stretching
1697 1760-1665
N-H Bending 1614 1650-1580
C-C
Stretching
1494 1550-1475
S=O
Stretching
1045 1070-1030
C-Cl
Stretching
754 850-550
FTIR OF Amlodipine besilate
DSC OF Amlodipine besilate
29
•DSC of Amlodipine besilate shows
endothermic peak at 205.08‫ﹾ‬c.

30. FTIR & DSC of Candesartan cilexetil
FTIR of Candesartan cilexetil
DSC of Candesartan cilexetil
Functional
group
Vibrational
Frequencies (cm-1)
Observed Reported
O-H
stretching
2985 3300-2500
C-H
Stretching
2939 3000-2850
C-C
Stretching
1442 1500-1400
C=O
Stretching 1751 1760-1690
C-O
Stretching
1203 1320-1000
C-N
Stretching
1072 1320-1000
30•DSC of Candesartan cilexetil
shows endothermic peak at
173.70‫ﹾ‬c.

31. FTIR & DSC of Cross carmelose Sodium
Functional
group
Vibrational
Frequencies(cm-1)
Observed Reported
O-H
stretching
3333 3500-3200
C-H
Stretching
2901 3300-2500
C=O
Stretching 1760 1760-1665
C-C
Stretching
1428 1500-1400
C-O
Stretching
1059 1320-1000
FTIR of Cross carmelose Sodium
DSC of Cross carmelose sodium
31•DSC of Crosscarmelose Sodium shows
endothermic peak at 79.59‫ﹾ‬c.

32. FTIR & DSC of Ethyl Celluose
FTIR of Ethyl cellulose
DSC of Ethyl cellulose
Functional
group
Vibrational
Frequencies(cm-1)
Observed Reported
O-H
stretching
3481 3500-3200
C-H
Stretching
2879 2500-3300
C-O
Stretching
1242 1320-1000
32
•DSC of Ethyl cellulose shows
endothermic peak at 79.09‫ﹾ‬c & 112.06‫ﹾ‬

33. FTIR & DSC of HPMC
FTIR of HPMC
DSC of HPMC
Functional
group
Vibrational
Frequencies(cm-1)
Observed Reported
O-H
stretching
2830 3300-2500
C-H
Stretching
2830 2830-2695
C-C
Stretching
1461 1500-1400
C-O
Stretching
1042 1320-1000
33
•DSC of HPMC shows endothermic peak
at 200.01‫ﹾ‬c.

34. Compatibility study
FTIR of Physical mixture
Functional
group
Vibrational
Frequencies(cm-1)
Observed Reported
C-H
Stretching
2939 3000-2850
C=O
Stretching
1753 1760-1690
N-H
Bending
1612 1650-1580
C-C
Stretching
1477 1400-1500
C-O
Stretching
1277 1320-1000
S=O
Stretching
1040 1070-1030
C-Cl
Strecting
750 850-550
34

35. FTIR of optimized formulation
Functional
group
Vibrational
Frequencies(cm-1)
Observed Reported
O-H
stretching
3398 3500-3200
C-H
Stretching
2975 3000-2850
C=O
Stretching
1753 1760-1690
C-C
Stretching
1421 1500-1400
C-O
Stretching
1276 1320-1000
S=O
Stretching
1023 1070-1030
C-CL
Stretching
696 850-550
FTIR of Formulation
DSC of Formulation
35
•DSC of Formulation shows endothermic
peak at 168.33‫ﹾ‬c & 205.15‫ﹾ‬c.

36. Sr.No Batches Angle of
Repose
Density (gm/ml) Compressibil
-iy
Index
Hausner’s
RatioBulk Tapped
1 F1 27.93±1.305 0.407±0.0063 0.514±0.018 20.70±3.953 1.26±0.065
2 F2 29.32±0.883 0.357±0.0051 0.541±0.041 33.81±5.564 1.51±0.125
3 F3 28.11±1.370 0.403±0.0063 0.508±0.010 20.51±1.471 1.25±0.020
4 F4 29.03±0.772 0.372±0.0051 0.576±0.023 35.63±1.531 1.55±0.036
Pre-compression parameters
Sr. No Batches Tablet Dimension Hardness
(kg/cm2)
Friability
(%)
Water
absorptionDiameter (mm) Thickness (mm)
1 F1 8.729±0.01 4.715±0.008 2.1±0.086 0.173 51.61±4.62
2 F2 8.736±0.02 5.326±0.012 2.05±0.086 0.452 28.58±0.08
3 F3 8.764±0.01 5.323±0.011 1.91±0.144 0.382 65.15±2.36
4 F4 8.768±0.01 5.373±0.008 2.05±0.086 0.692 20.94±18.5
Sr.No. Batc
hes
Wt variation
test (%)
Wetting
Time
DT Drug Content
AB CC
1 F1 0.287±0.001 163.66±10.01 72.33±2.51 90.45±2.4 88.12±4.02
2 F2 0.287±0.00099 197.66±16.62 91.66±2.08 88.31±5.20 89.79±2.61
3 F3 0.287±0.00091 150±4 57.33±1.52 95.25±3.67 91.46±5.73
4 F4 0.287±0.0011 206.66±18.58 93±2.645 95.25±4.41 87.70±3.31
Post-compression parameters
36

37. Dissolution Studies of
Formulation
Sr.
No.
Tim
e
(Mi.
)
% CDR
at 254 λ max.
% CDR
After
stability
F1 F2 F3 F4 F3
1 0 0 0 0 0 0
2 10 45.66 37.79 54.41 34.29 53.25
3 20 58.78 46.53 68.40 46.51 66.49
4 30 69.28 57.91 77.15 52.66 74.27
5 40 80.65 65.78 84.15 60.53 83.24
6 50 83.28 70.12 87.65 65.78 86.59
7 60 88.53 75.40 91.15 71.03 90.43
8 70 91.15 81.43 93.77 75.40 92.47
9 80 93.77 83.28 97.27 79.78 96.25
10 90 95.52 85.03 98.15 83.28 97.55
% CDR of Candesartan cilexetil
% CDR of Candesartan cilexetil after stability
37

38. Dissolution Studies of
Formulation
Sr.
N
o.
Time
(Min.
)
% CDR from Fast Disintegrating
Tablet
At 237 λ max
% CDR
after
stability
F1 F2 F3 F4 F3
1 0 0 0 0 0 0
2 10 58.22 41.19 60.44 41.19 59.99
3 20 70.07 51.78 72.96 58.52 71.45
4 30 78.73 58.52 83.55 64.29 82.45
5 40 84.51 69.11 89.32 74.88 87.56
6 50 91.25 74.88 93.17 78.73 92.63
7 60 93.17 78.73 96.06 85.47 96.48
8 70 95.10 87.40 97.98 88.36 97.10
9 80 97.98 88.36 98.95 98.32 97.69
10 90 97.98 88.36 98.95 91.25 97.89
% CDR of Amlodipine besilate
% CDR of Amlodipine besilate after stability
38

39. 39
Batch First order (R2) Zero order (R)
Candesartan Amlodipine Candesartan Amlodipine
F1 0.991 0.985 0.770 0.670
F2 0.979 0.971 0.834 0.825
F3 0.991 0.987 0.700 0.635
F4 0.982 0.985 0.969 0.894
Kinetics Model
Amlodipine besilate
Amlodipine besilateCandesartan cilexetil
Candesartan cilexetil

40. Analytical method development
Trial 1:
Chromatographic Condition:
Column:C18 (250 mm x 4.6,5um)
Mobile phase: Methanol : Water [70:30 pH 4.0]
Flow rate: 0.8 ml/ min
Detection wavelength: 237 nm
Column temperature: 250 c
Injection volume: 20 μl
Run time: 10 min
Observation:
To above chromatogram only one peak of Amlodipine Besilate was eluated and second
peak of candesartan cilexetil was not eluated
Amlodipine besilate
Peak RT Area Efficienc
y
Tailing
Amlodipine 3.901 122.996 4697 1.46
Candesarta
n
- - - -
40

41. Trial 2:
Chromatographic Condition:
Column: C18 (250 mm x 4.6,5 um)
Mobile phase: Acetonitrile : Water[90:10]
pH- 4.8
Flow rate: 0.8 ml/ min
Detection wavelength: 237 nm
Column temperature: 25‫ﹾ‬ c
Injection volume: 20 μl
Run time: 10 min
Observation-
Amlodipine Besilate and Candesartan
cilexetil
both drug are eluted but resolution was
low and Amlodipine besilate showed
broad peak further trial was carried out.
Amlodipine besilate
Candesartan cilexetil
41
Sr
No
Pea
k
RT Peak
Area
Efficienc
y
Tailin
g
1 AB 2.53 136.25 1894 1.41
2 CC 5.89 108.80 12649 1.16

42. Trial 3:
Chromatographic Condition:
Column: C18 (250 mm x 4.6,5um)
MP: Methanol: Acetonitrile : Water [70:20:10]
pH- 4.4
Flow rate: 0.8 ml/ min
Detection wavelength: 237 nm
Column temperature: 250 c
Injection volume: 20 μl
Run time: 10 min
Observation-
Amlodipine Besilate and Candesartan Cilexetil both peak are eluted but system
suitability parameter was not pass with in limit so further trial was carried out.
Amlodipine besilate & Candesartan cilexetil
42
Sr
No
Pea
k
RT Peak
Area
Efficienc
y
Tailing
1 AB 2.433 155.51
2
2711 1.46
2 CC 7.100 112.411 12983 1.16

43. The follwing chromatographic conditions were established by trial and error and
kept constant through out the method
Chromatographic Condition:
Column: C18 (250 mm x 4.6,5um)
Mobile phase: Acetonitrile : Water [80:20]
pH- 4.2
Flow rate: 0.8 ml/ min
Detection wavelength: 237 nm
Column temperature: 250 c
Injection volume: 20 µl
Run time: 10 min
Observation-
Amlodipine Besilate and Candesartan Cilexetil both peak are eluted and system
suitability
parameter was pass with in limit so this trial batch mobile phase is selected .
Amlodipine besilate
Candesartan cilexetil
43
Peak RT Peak
Area
Efficienc
y
Tailin
g
AB 2.611 38.304 5012 0.81
CC 8.531 317.51 16423 1.24

44. • Preparation of standard drug solution:
System suitability parameters were determined by preparing working sample solution
from the stock solution of Amlodipine besilate (2µg/ml) and Candesartan cilexetil
(5µl/ml).
Table : System Suitability for Amlodipine besilate & Candesartan cilexetil
Sr No Amlodipine besilate
RT Peak Area Efficiency Tailing
Factor
1 2.511 48.714 2891 1.145
2 2.525 48.134 2865 1.123
3 2.549 47.128 2893 1.142
4 2.552 48.119 2861 1.141
5 2.512 47.120 2889 1.139
Mean 2.529 47.843 2879 1.138
SD 0.0197 0.698 15.46 0.00866
%
RSD
0.778 1.45 0.536 0.760
Limit NMT 1 % NMT 2 % MT 2000 NMT2
System Suitability Testing
44
Amlodipine besilate

45. 45
Candesartan cilexetil
RT Peak Area Efficiency Tailing Factor Resolution
8.360 129.89 15800 1.302 16.441
8.367 131.54 15869 1.299 15.941
8.367 131.54 15894 1.309 16.430
8.365 131.53 15863 1.299 16.601
8.360 129.89 15867 1.305 15.539
8.363 130.88 15854 1.302 16.190
0.0035 0.901 34.889 0.00426 0.440
0.0418 0.688 0.22 0.327 2.717
NMT 1 % NMT 2% NMT 2000 NMT 2 MT 2
Candesartan cilexetil

46. Chromatographic Condition:
Column: C18 (250 mm x 4.6,5um)
Mobile phase: Acetonitrile : Water [80:20]
pH- 4.2
Flow rate: 0.8 ml/ min
Detection wavelength: 237 nm
Column temperature: 250 c
Injection volume: 20 μl
Run time: 10 min
Observation:
Did not found interfering peaks in blank of thEse drugs So method is said to be
specific
Specificity
46

47. Calibration Curve of Amlodipine besilate
Sr
No.
Con. Retention
time
Peak
area
Efficiency Tailing
1 2 2.513 47.610 2891 0.998
2 4 2.550 85.028 1871 0.956
3 6 2.547 125.950 2582 0.984
4 8 2.553 170.991 2316 0.988
5 10 2.547 210.156 2436 0.996
y = 20.88x + 2.205
R² = 0.999
0
50
100
150
200
250
0 2 4 6 8 10 12
Area
Concentration
Calibration curve of Amlodipine besilate
Absorbance
Linear (Absorbance)
Linearity of Amlodipine besilate
λ max (nm) 237nm
(R2) 0.999
Regressio
n equation
y= 20.88x+2.205
Intercept
(a)
2.205
Slope (b) 20.88
47

48. Calibration Curve of Candesartan cilexetil
Linearity of Candesartan cilexetil
Sr.No. Conc Retention
Time
Peak Area Efficiency Tailing
1 5 8.467 131.548 15800 0.995
2 10 8.460 269.277 16468 0.956
3 15 8.467 416.236 14468 0.982
4 20 8.467 568.657 15800 0.997
5 25 8.473 718.691 16495 0.995
y = 28.867x - 10.104
R² = 0.9992
-100
0
100
200
300
400
500
600
700
800
0 5 10 15 20 25 30
Area
Concentration
Calibration curve of Candesartan cilexetil
Absorbance
Linear (Absorbance)
λ max (nm) 237nm
(R2) 0.999
Regressio
n equation
y= 28.86x-10.10
Intercept
(a)
10.10
Slope (b) 28.86
48

49. Five sample solution of pure Amlodipine besilate and Candesartan cilexetil were
injected five times and analyzed.
Sr.No. Peak area at 237 nm Limit
Amlodipine besilate Candesartan cilexetil
1 561.188 852.880
NMT 2.0 %
2 560.146 856.692
3 560.168 873.923
4 549.031 852.785
5 548.056 874.950
Mean 555.717 862.950
% RSD 1.18 % 1.30 %
System precision
49

50. Repeatability precision
Sr. No. Peak area Limit
Amlodipine besilate Candesartan cilexetil
1 277.488 852.880
NMT 2.0 %
2 281.354 856.692
3 282.955 873.923
4 282.365 852.785
5 280.359 874.950
Mean 280.904 862.246
% RSD 0.765 % 1.30 %
Five sample solution of pure Amlodipine besilate and Candesartan cilexetil were
injected five times and analyzed.
50

51. Table No: Accuracy of Amlodipine Besilate and Candesartan
Cilexetil%
level
Amount of standard
drug added
Amount of added
drug found
% Recovery
AB CC AB CC AB CC
80 8 20 7.912 19.72 98.90 98.60
100 10 25 9.947 24.90 99.47 99.60
120 12 30 12.62 30.26 105.18 100.86
Accuracy
Assay
Sr. No. Amlodipine Besilate Candesartan
Cilexetil
Area % Assay Area % Assay
1 54.522 100.2 75.903 99.33
2 53.665 98.58 74.785 98.04
3 53.668 98.58 74.762 98.01
4 53.616 98.48 75.762 99.31
5 54.718 100.59 74.996 98.21
Mean 54.037 99.286 75.241 98.58
SD 0.536 1.022 0.549 0.679
RSD 0.991 0.010 0.729 0.688
51

52. Robustness – Flow rate (± 0.8
ml/min)
Sr No 0.6 ml/min 1.0 ml/min
AB CC AB CC
1 275.303 816.088 280.488 852.880
2 276.125 817.264 281.354 856.692
3 275.025 819.201 280.955 873.923
4 275.489 819.201 281.359 852.785
5 275.354 817.364 282.365 874.950
Mean 275.459 817.837 281.304 862.246
SD 0.4087 1.371 0.692 11.24
52

53. Robustness – Wavelength (± 2 nm)
Sr No 235 nm 237 nm
AB CC AB CC
1 561.188 852.880 277.488 852.880
2 560.146 856.692 277.135 852.469
3 560.168 873.923 277.168 852.147
4 549.031 852.785 277.138 852.364
5 548.056 874.950 277.489 852.321
Mean 555.717 862.246 277.283 852.436
SD 6.571 11.24 0.187 0.0273
% RSD 1.18 1.30 0.067 0.0320
53

54. LOD/LOQ
Sr.No
.
Sample concentration Retentio
n time
Peak
area
LOD LOQ
1 Amlodipine
besilate
2 µg/ml 2.437 48.714 0.110 0.093
2 Candesartan
cilexetil
5µg/ml 8.367 131.548 0.093 0.312
54

55. • Acid Degradation Study
• Thermal Degradation Study
• Base Degradation Study
• Photo Degradation Study
Stability Studies
55

56. Degradation data
Sr.No Type of
Degradation
Amlodipine Besilate Candesartan Cilexetil
% obtained % degraded % obtained % degraded
1 Acid 95.37 % 4.63 % 94.18 % 5.82 %
2 Alkali 84.66 % 15.34 % 81.98 % 18.02 %
4 Thermal 77.71 % 22.29 % 82.48 % 17.52 %
5 Photolight 96.357 % 3.643 % 98.789 % 1.211 %
56

57. Parameters Amlodipine besilate Candesartan cilexetil
λ max 237.5 254
Calibration curve Methanol Y=0.036x-0.005 Y=0.023x-0.001
Phosphate buffer 6.8 Y=0.093x-0.022 Y=0.064x-0.025
Pre-compression
parameter
Angle of Repose 28.11±1.370
Bulk Density 0.403±0.0063
Tapped Density 0.508±0.010
Compressibility Index 20.51±1.471
Hausners ratio 1.25±0.020
Post-
Compression
Parameters
Tablet Dimension 8.764±0.01
Tablet Thickness 5.323±0.011
Hardness 1.91±0.144
Friability 0.382
Water Absorption 65.15±2.36
Weight Variation 0.287±0.00091
Disintegrating Time 57.33±1.52
Wetting Time 150±4
SUMMARY
57

58. Parameters Amlodipine besilate Candesartan cilexetil
Linearity Range 2-10μg/ml 5-25μg/ml
Regression equation y= 20.884x + 2.205 y=28.867x-10.104
Regression coefficient 0.999 0.999
Specificity Specific Specific
Repeatability % RSD 1.18 1.30
Intermediate precision % RSD 0.765 1.30
Accuracy-% Recovery 101.18 99.96
Assay 99.28 % 98.58 %
Robustness Flow Rate Plus 0.245 1.30
Minus 0.148 0.163
λ max Plus 0067 0.032
Minus 1.18 1.30
LOD
LOQ
0.110 0.093
0.093 0.312
Degradation study
Acidic 4.63 % 5.82 %
Alkali 15.34 % 18.02 %
Thermal 22.29 % 17.52 %
58

59. 59
CONCLUSION
Fast Disintegrating Tablet Significantly improve dissolution rate and
improve
onset of action for better results
Preformulation study like solublility,melting point of Amlodipine besilate &
Candesartan cilexetil complied with official standard
FTIR & DSC analysis study shows there is no any interaction between
drug & excipient
Formulated tablet of Amlodipine besilate & Candesartan cilexetil shows
complience for various parameters like disintegration time, hardness,
dimension , dissolution rate as per Pharmacopeial specification
Developed chromatographic method is simple, precise, sensitive, reliable
for routine analysis of formulation
All the parameters of system suitability are with in the limit hence it can be
conclude that all the system is suitable for routine analysis to perform assay

60. 1. Dufton J. The pathophysiology and pharmaceutical treatment of hypertension. Accreditation council for
pharmacy education. 2011: 1-11.
2. Clinical guidelines for the management of hypertension. World health organization regional office for
the eastern mediterranean cairo. 2005: 1-97.
3. Vimal vv, aarathi ts, john sb. Superdisintegrants in fast disintegrating drug delivery system: A brief
review. Int. J. Pharm.2013; 3(2): 380-385
4. Nagar p,singh k,chauhun I, verma m,yasir M, khan a,sharma R, gupta N.Orally disintegrating tablets :
formulation, preperation technique and evaluation. J. Appl. Pharm. Sci.2011;1(4): 35-45
5. Nasir A, gohar UF, ahmad B, A review article on superdisintegrants. Int. Res. J. Pharm.Sci.1-11
6. Kaur v,mehera N. A review on : importance of superdisintegrant on immediate release tablets. Int. J. Res.
Sci. Innovation.2016; 3(2): 39-43
7. Rawat S, derle DV, fukte SR, shinde PR, parve BS. Superdisintegrants: an overview. World. J. Pharm.
Pharm. Sci.2014; 3(5):263-278
8. Sharma D, kumar D, singh M, singh G, rathore MS. Fast disintegrating tablets: A new era in novel drug
delivery system and new market opportunity. J. Drug delivery ther. 2012; 2(3): 74-86
9. Panigrahi R,A review on fast dissolving tablet. Webmed central.29 sep. 1-17
11. Abay FB, ugurlu T. Orally disintegrating tablets: A short review. J of pharmaceutical & drug
development.2015;3(3) : 2348-9782Khanna K, Xaveir G, Kumar S, Patel A, Khanna S, Goel V, Goel B. Fast
disintegrating tablets-A novel approach. Int. J. Pharm. Res. Appl. Sci.2016; 5(2): 311-322
12. Masih A, kumar A, Singh S, Tiwari AK. Fast dissolving tablets: A review. Int. J. Curr. Pharm. Res.2017;9(2):
8-18
13. Gupta AK, Mittal A,Jha KK. Fast dissolving tablets: A review the Pharma. Innovation.2012; 1(1):1-8
60
Reference

61. 14. Awasthi R, Sharma G, Dua K, Kulkarni G. Fast disintegrating drug delivery system: A review with special
emphasis on fast disintegrating tablets. J of Chronotherapy and drug delivery. 2013;4(1): 2249-6785
15. Mohanachandran PS, Sindhumol PG, Kiran TS. Superdisintegrants: An overview. Int. J. Pharm. Sci. Rev.
Res. Jan-feb. 2011;6(1)105-109
16. Hirani JJ, Rathod DA, Vadalia KR. Orally diintegrating tablets: A review .Trop. J. Pharm. Res. April
2009;8(2):161-172
17. Alton;s Pharmaceutics, The Design and Manufacure of Medicine,Bipharmaceutics and Pharmacokinetics,
Elsevier Publication.III edition.2007;441-482
18. Ansel’s Pharmaceutical dosage forms and drug delivery systems, South Assian Edition. 9th edition; 225-
256.
19. Kumar L, Singh V, Kumar RM. Formulation and evaluation of oral disintegrating tablet of candesartan
cilexetil. World. J. Pharm. Res.2015;4(2):1158-1170
20. Jasem AM, Ghareeb MM. Preperation and characterization of orodispersible tablets of candesartan
cilexetil by direct compression method. Int. J. Pharm. Pharm. Sci. 2013;5(1):328-333.
21. Jampani N, Bonthu RK, Reddy BM. Formulation and evaluation of candesartan cilexetil immediate
release tablets. Int. Res. J. Pharm.2012;3(7):271-284.
22. Reddy GA, Chowdary YA. Formulation and evaluation of oral fast disintegrating tablet by using
amlodipine besylate solid dispersion by direct compression. Scholar research library.2012,4(2):683-694.
23. Kalyan P, Narendra R. Formulation and evaluation of bilayered tablet of candesartan cilexetil. Int. J.
Pharm. Technol.2016/18/2;8(1):10282-10303.
24. Kumar L, Kumar RM, Godara A, Singh V, Agarwal A. Formulation and evaluation of rapid disintegrating
tablet of candesartan cilexetil for the management of hypertension. J. Chem. Pharm. Res.2014; 6(8):421-
428.
25. Kumar RB. A review on fast disintegrating tablets: A new era in novel drug supply process. Research and
review: journal of Pharmaceutical and nanotechnology.2016;4(2):1-8.
26. Harkare BR, kulkarni AS, majumdar SH, aloorkar NH. Effect of mannitol and MCC on rapidly
disintegrating tablets. World. J. Pharm. Res.2014;3(6):1040-1065.

62. 27. Kumar Rb, A Review On Fast Dissolving Tablet: A New Era In Novel Drug Supply Process. J. Pharm.
Nanotechnol. 2016;4(2): 1-8.
28. Skoog Da , Holler Fj, Crouch Sr .Instrumental Analysis . Cengage Learning India Private Limited , New
Delhi .2010 ; (6) : 752 -777 ,806 -842 .
29. Stanley Kl, Godwin Wf..Hplc In The Pharmaceutical Industry .Usa: Marcel Dekker. 1991; V(47) :241-295
30. .Gilbert Mt .High Performance Liquid Chromatography
31. Connors Ak. A Textbook Of Pharmaceutical Analysis. A Wiley-inter Sciences Publication. 1999; (3) :373 -
416.
32. Willard Hh, Metritt Ll, Dean Ja ,Settal Fa. Instrumental Method Of Analysis. CBS Publishers And
Distributers,new Delhi .1986;(7) : 513 -534 ,580-608.
33. Ewing Gw,caze J. Analytical Instrumentation .Florida USA. Mcgra –Hill International
Edition.1995;(5):696-708
34. Day RA. Quantitative Analysis .Prentice-hall Of India Private Limited, New Delhi .(6) : 556 -570 .
35. Mermet JM ,Otto M, Valcarcel M ,Kellner R, Widmer HM .Analytical Chemistery, A Modern Approach
To Analytical Science .WILEY-VCH Verlag Gmbh And Co.Kgaa ,USA .2004 ;( 2) : 22-36 ,559-605 .
36. Svehla G.Vogel’s Qualitative Inorganic Analysis .Pearson Education ,Ltd ,South Asia .(7) : 66-70
37. Mukherjee PK .Quality Control Of Herbal Drugs .Business Horizons ,New Delhi .2002 ; (1) : 426 -512.
38. Munson Jw .Pharmaceutical Analysis Modern Methods .Informa Healthcare .2012 ;Vol (11) : 105.
39. Carstensen Jt .Drug Stability Principles And Practices .Marcel Dekkers Inc ,(2) : 122 -156.
40. Potdar M .Pharmaceutical Quality Assurance .Nirali Prakashan ;2007 (2): 81-83
41. Ashutoshkar .Pharmaceutical Drug Analysis .New Age International Publishers ,(2) 473.
42. Sangeetha M, Reichal Cr, Indulatha Un, Thirumoorthy N. Development And Validation Of RP-HPLC
Method-an Overview. J. Pharm. Anal.2014;3(4): 8-14.
43. Phani Rs, Prasad Kr, Useni Rm. Scientific Approach For RP-HPLC Method Development:complete
Review. Int. J. Sci. Innovations. Discoveries.2012:2(6):218-228
44. Touchstone JC. History Of Chromatography. J. Liq. Chromatogr. 16(8): 1647-1665
45. Http://En.Wikipedia.Org / Wiki/Chromatography.
62

63. 63
46. Coskun O. Separation techniques: chromatography. Northem clinics of astanbul.2016;3(2): 156-160.DOI:
10.14744/nci.2016.32757.
47. Magdeldin S, Moser A. Affinity chromatography: principles and applications.2012: 1-29
48. Claessens HA. Characteristics of stationary phases for reversed phase liquid chromatography: column
testing, classification and chemical stability Eindhoven: Technische Universiteit Eindhoven DOI:
10.6100/1R/8234 27 Nov 2017.
49. Gocan S. Stationary phases for TLC. J. Chromatogr. Sci.: Nov-Dec:2002: 2-12.
50. Pathy KS. Basic skills training guide-HPLC method development and validation : An overview.May.2013
51. Mendham J, Denney RC, Barners JD, Thomas MJ. Vogel’s textbook of quantitative chemical analysis,
Pearson’s publication.6th edition.292-312.
52. Sabir AM, Moloy M, Bhasin PS. HPLC method development and validation: An overview. Int. Res. J.
Pharm. 2013;4(4): 39-46.
53. Munson JW. Pharmaceutical Analysis. Informa healthcare: 2012.Vol-11: 15-154.
54. Michael Swartz. HPLC detector: A brief review. J. Liq. Chromatogr. Relat. Technol.2010; Vol-33: 1130-
1150.
55. Ramni K, Kaur N, Upadhaay A, Suri O, Thakker A.HPLC performance liquid chromatography detector: A
review. 2011; Vol-2 (5): 1-7
56. Bhosale SD. Development of validated analytical methods for some drugs and their
formulations.[doctoral thesis] Baroda: The maharaja sayajirao university of baroda, Pharmacy
department Faculty of technology and engineering;2011.
57. Patel RM, Patel PM, Patel NM. Stability indicating HPLC method development-A review. Int. Res. J.
Pharm.2011;2(5): 79-87.
58. Gupta V, Jain Ad, Gill Ns. Development And Validation Of Hplc Method-a Review. Int. Res. J Pharm.
Appl. Sci. 2012;2(4):1725.
59. Thammana M.A Review On High Performance Liquid Chromatography. J Pharm. Anal.2016;5(2): 22-
28.

64. 60. Shrivastava A, Gupta Vb. Hplc: Isocratic Or Gradient Elution And Assessment Of Linearity In Analytical
Method. J. Adv. Sci. Res.2012;3(2):12-20.
61. Agarwal V, Sharma D. Stability Testing Of API. J. Pharm. Sci. Innovation. March-april.2012;1(2):18-23.
62. Deokate U, Gorde Am. Forced Degradation And Stability Testing: Strategies And Analytical Perspective.
Int. J. Pharm. Rev. Res.2014:26(2);242-250
63. Prathap B, Dey A, Srinivaso GH. A Review- Importance Of RP-HPLC In Analytical Method Development.
Int. J. Novel Trends Pharm. Sci. Feb:2013: 3(1);15-23.
64. Bhatt Ad, Rane Si. Qbd Approach To Analytical RP-HPLC Method Development And Its Validation. Int. J.
Pharm. Pharm. Res.2011;3(1):179-187.
65. Chandrul Kk, Srivastava B. A Process Of Method Development: A Chromatographic Approach. J. Chem.
Pharm. Res.2010;2(2): 519-545.
66. Sharma Mk, Murugeson M. Forced Degradation Study An Essential Approach To Develop Stability
Indicating Method. Journal Of Chromatographic Separation Techniques.2017;8(1):1-3
67. Schellinger AP, Carr PW. Isocratic And Gradient Chromatography : A Comparison In Terms Of
Speed,retention Reproducibility And Quantitation. J. Chromatogr. 2016:253-266. Doi:
10.1016/J.Chroma.2006.01.047.
68. Ich Harmonized Tripartite Guidelines, Validation Of Analytical Procedure: Text And Methodology Q2
(R1),ich Steering Committee ,Genova, November 2005.
69. Kotecha B, Pamphar M, Zala G, Faldu S. Qbd Q Absorbance Ratio Spectrophotometric Method For The
Simultaneous Estimation Of Amlodipine Besylate And Candesartan Cilexetil In Synthetic Mixture;
Pharmatutor Magazine;2014;2(5): 167-178
64

65. 65
70. Indian Pharmacopia. Government Of India Ministry Of Health And Family Welfare. The Indian
Pharmacopoeia Commission. Ghaziabad 2010;180
71. Sweetman Sc,martindale. The Complete Drug Reference. Pharmaceutical Press London 2014;(13):
72. Http://Www.Drugs.Com/ Monograph Amlodipine
73. Http://En.M.Wikipedia.Org/Wiki/Amlodipine
74. Http://Www.Drugbank.Co/ Drug DB00381 Amlodipine
75. Http://Www.Drugbank.Co/ Drug DB00796 Candesartan Cilexetil
76. Http:// Pubchem.Ncbi.Nlm.Gov
77. Varma KV. Excipients Used In The Formulation Of Tablets: Res. Rev: J. Chem. 2016;5(2): 143-154
78. Remington The Science And Practice Of Pharmacy,21th Edi, Vol I, Lippincott Williams And Wilkins. B.I
Publication Pvt Ltd: 917
79. Raymond C.R,paul J.S, Marian E.Q.Handbook Of Pharmaceutical Excipients. London Pharmaceutical
Press.2009;(6):
80. British Pharmacopoeia. British Pharmacopoeia Commission Office London.2015;i:153,393.
81. Varma K. Excipients Used In TheFormulation Of Tablets. Reserch And Review: J.Chem.2016;5(2):143-154.
82. Maulik R, Machhaliya Ry,patel Cn,daraji Hm.Formulation And Evaluation Of Sublingual Tablet Of
Candesartan Ciexetil .Int. J. Pharm. Res. Bio-sci.2014;3(2):900-925.

66. 83. Madhurya D, Vineela G, Chaitanya GS, Fatima K, Sahithi G.Formulation And Development Of Amlodipine
IR Tablet As Per 22 Factorial Design (Selection Of Best Binder And Disintegrant) Eur. J. Biomed. Pharm.
Sci.2015;2(3):300-307
84. Reddy Ga,naveen KJ, Chowdhary YA. Formulation And Evaluation Of Oral Fast Disintegranting Tablets By
Using Amlodipine Besylate Solid Dispersion By Direct Compression Method. Der. Pharm. Lett. Scholar
Research Library.2012;4(2): 683-694.
85. Patil Bs, Raghevendra Ng. Formulation And Evaluation Of Fast Dissolving Tablet Of Candesartan Cilexetil
Using Natural And Synthetic Superdisintegrant. J. Appl. Pharm. 2011;3 (3):250-261
86. Vishnu P, Naveen B, Reddy S. Formulation And Evaluation Of Candesartan Cilexetil Floating Tablets By
Melts Granulation Technique. Int. J. Res. Pharm. Chem. 2015;5(5):373-379.
87. Shukla S, Pandya V, Bharadia P,mishra S,bhatt D,jonwal N. Formulation ,Optimization And Evaluation Of
Bi-layer Immediate Release Tablets Of Telmisartan And Amlodipine Besilate Using Full Factorial Design.
Int. J Pharm. Pharm. Sci. Res.2013;3(2):72-78
88. Blessy M, Patel RD, Prajapati PN. Agrawal YK. Development Of Forced Degradation And Stability
Indicating Studies Of Drugs-a Review. J. Pharm. Anal. 2014 ;4(3):159-165.
89. Akula G,kandikonda S, Bhupati S, Kumar Rr ,Kumar Sk.RP-HPLC Method Development And Validation Of
Candesartan Cilexetil In Bulk And Their Pharmaceutical Dosage Forms. Int. J. Pharm. Sci.
Res.2010;1(12):191-196.
90. Hussain S, Munjewar Rr ,Farooqui M.Development And Validation Of A Simultaneous HPLC Method For
Quantification Of Amlodipine Besylate And Metoprolol Tartrate In Tablets. J. Pharm. Sci. Tech. 2012;
66

67. 90. Pambhar M,zala G,faldu S.Q -Absorbance Ratio Spectrophotometric Method For The Simultaneous
Estimation Of Amlodipine Besylate And Candesartan Cilexetil In Synthetic Mixture. Pharma Tutor
Magazine.2018 ;2(5):167-178
91. Kotthireddy K, Devi RB. Stability Indicating RP-HPLC Method Development And Validation For The
Simultaneous Estimation Of Candesartan Cilexetil And Hydrochlorothiazide In Bulk And Tablet Dosage
Form. Der. Pharma. Lett. 2015; 7 (12):114-121.
92. Latha M,gowri Sd.Stability Indicating RP-HPLC Method For The Determination Of Candesartan In Pure
And Pharmaceutical Formulation. Int. .J..Pharm. Ind. Res.2011;1(4):344-349.
93. Nabanitha M,Haque A, Bakshi V. Method Development, Validation and Stability Analysis by RP-HPLC
Method for the Simultaneous Estimation of Candesartan Cilexetil and Levocetrizine Hydrochloride. Int. J.
Med. Nanotechnol, Mednano Publications.2014; 1(3):145-151.
94. Shaikh MM,Master S,Chaudhary AM.Development and validation of RP-HPLC method for simultaneous
estimation of Amlodipine besylate and Irbesartan. Int. Bull. Drug Res.2014;4(7): 1-15.
95. Srivani A, Hazari S, Malichetti S.Development and validation of RP-HPLC Method for simultaneous
estimation of Atenolol and Amlodipine in bulk and tablet dosage form. Int. J. Pharm.2014;4(1):265-269
96. Sasidhar RL,Dharaa, B.Deepti, K Tejaswi, JSuhasini. Development and Validation of RP - HPLC Method for
the Simultaneous Determination Of Hydrochlorothiazide, Amlodipine Besylate and Telmisartan in Bulk
and Pharmaceutical Formulation. Orient. J. Chem.2014;30 (4): 1815-1822.
97. Panchumarthy R, Naga CN, Pravallika D, Sri DN.A review on step by step analytical method validation.
IOSR J. Pharm. 2015;5(10):7-19.
98. Patil PN. HPLC method development-a review.Journal of Pharmaceutical Reserch and Education.2017;
1(2): 243-260
99. Ehlag DE, Atiatalla OA,Mahmoud MB. RP-HPLC method development and validation for simultaneous
estimation of Candesartan cilexetil and Hydrochlorothaizide tablet dosage form: American journal of
Pharma tech Research.2015;5(3):1-11 67

68. 100.Kumar GM, Meechel A, Vasantha kumar PM, Kumar DA, Jyothi N,Seshagiri VL. Development and
validation of an RP_HPLC method for the determination of the Candesartan cilexetil in tablet dosage
form.Int J.Chem.Sci.2010:8(4):2245-2252
101.Saroha K, Mathur P.Mouth Dissolving Tablet: An overview on Future Compaction in oral
formulation Technogies;Der Pharmacia Sinica,2010; 1(1):179-187
102.Rai R,Chirra R,Thanda V, Fast Dissolving Tablets: A Novel Approach To Drug Delivery : A
Review;2012;3(1):23-32
103.Duppala L,Kumar D. Fast Dissolving Dosage Form. An Overview; World J Pharm.
Res.2016;5(10):1185-1200
104.Kumar V,Kumar R.Fast Dissolving Tablets: A Novel Approach to Enhance the Bioavaliability of
Poorly Soluble Drugs: Euro. J. Pharm. Med. Res.2017;4(2):274-294
68